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Pediatric phase I trial, pharmacokinetic study, and limited sampling strategy for piritrexim administered on a
P C Adamson1, F M Balis, J Miser
1Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892.
Insights
This Phase I trial determined the recommended dose of piritrexim (an antifolate drug) for pediatric cancer patients. A dose of 20 mg/m2/dose is suggested for future studies, with monitoring to prevent toxicity.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Clinical Trials
Background:
- Piritrexim is an orally administered antifolate medication.
- Children with refractory malignancies were enrolled in this multi-institutional Phase I trial.
Purpose of the Study:
- To evaluate the safety and determine the recommended dose of piritrexim in pediatric cancer patients.
- To assess the pharmacokinetics and pharmacodynamics of piritrexim in this population.
Main Methods:
- A dose-escalation Phase I trial was conducted with piritrexim in children aged 3.5-20 years.
- Pharmacokinetic monitoring and analysis of dose-limiting toxicities (myelosuppression, mucositis) were performed.
- A limited sampling strategy for predicting area under the concentration-time curve (AUC) was prospectively tested.
Main Results:
- The recommended dose for Phase II trials was determined to be 20 mg/m2/dose.
- Dose-limiting toxicities were observed at 25 mg/m2/dose, but not at lower doses.
- A strong correlation was found between trough piritrexim concentration and dose-limiting toxicities, with >0.5 microM predicting toxicity.
Conclusions:
- Therapeutic drug monitoring of piritrexim is crucial for optimizing dosage and schedule in pediatric patients.
- The limited sampling strategy for AUC prediction proved highly effective.
- Piritrexim demonstrates a linear pharmacokinetic profile and a clear relationship between concentration and toxicity.
Abstract:
Piritrexim, an orally administered, lipid-soluble antifolate, was evaluated in a multi-institutional phase I trial in children. The starting dose was 10 mg/m2/dose administered every 8 h daily for 5 days for 3 consecutive weeks, with dose escalations in increments of 5 mg/m2/dose. Eighteen patients (16 with metastatic sarcoma, 1 with acute lymphoblastic leukemia, and 1 with a brainstem glioma), 3.5-20 years of age, with malignancy refractory to therapy, were entered into the study. The dose-limiting toxicities (DLTs), which were myelosuppression and mucositis, occurred in 4 of 4 patients treated at the 25-mg/m2/dose level but in none of the patients treated at the 15- and 20-mg/m2/dose levels. The recommended dose for phase II trials is 20 mg/m2/dose. Pharmacokinetic monitoring was performed in 15 of the 18 children. The area under the concentration-time curve (AUC) was linearly related to the dose administered. Piritrexim was rapidly absorbed, with the median time to peak level occurring 1.5 h after an oral dose. The terminal half-life of piritrexim ranged from 1.5 to 4.5 h. A limited sampling strategy developed earlier, capable of predicting the AUC based on the plasma concentrations at 3 and 6 h after an oral dose, was prospectively tested in this trial and proved to be highly predictive of the AUC (r = 0.98, P = 0.0001). Pharmacodynamic-pharmacokinetic correlations were obtained after combining data from this and the prior phase I pediatric trial. Trough plasma piritrexim concentration strongly correlated with DLT (P = 0.0016). A trough plasma piritrexim concentration greater than 0.5 microM appeared to be predictive of toxicity. Eleven of 15 patients with trough concentrations exceeding this threshold experienced DLTs. Therapeutic drug monitoring may thus play an important role in adjusting the dose and schedule of piritrexim in future trials.